Certain 2-spiro-tetrahydro-halo-sulfamyl-quinazolinones



United States Patent Office 3,518,392 Patented June 30, 1970 3,518,392CERTAIN Z-SPIRO-TETRAHYDRO-HALO- SULFAMYL-QUINAZOLINONES Bola VithalShetty, Rochester, N.Y., assignor to Pennwalt Corporation, East Orange,N.J., a corporation of Pennsylvania No Drawing. C-ontinuation-in-part ofapplication Ser. No. 517,995, Jan. 3, 1966. This application Nov. 2,1967, Ser. No. 680,010

Int. Cl. C07d 51/48 US. Cl. 260-2565 4 Claims ABSTRACT OF THE DISCLOSUREA tetrahydro 6 sulfamyl-7-haloquinazolinone compound having diureticproperties with low potassium excretion, characterized by having aphenyl, or phenylalkyl group, which may be substituted or unsubstituted,in the 3-position, and having a di-alkyl, halogen substituted dialkyl,or a spiro group which may be carbocyclic or heterocyclic, in the2-position.

This application is a continuation-in-part of my copending applicationSer. No. 517,995, filed Jan. 3, 1966, now Pat, 3,360,518, which patentin column 7, lines 40 and 41 discloses compounds within the genericstructural formula of this application.

The invention relates to tetrahydro halosulfamyl quinazolinones havingdiuretic properties with low potassium excretion. More particularly theinvention relates to compounds of the group consisting of (A) compoundsof the formula:

in which R, is hydrogen, loweralkyl, loweralkoxyloweralkyl,phenylloweralkyl or phenylloweralkyl substituted with a loweralkyl or ahalogen attached to the phenyl moiety; R' is loweralkyl, loweralkylhaving a halogen attached to the alkyl group, such as chloromethyl,dichloromethyl, trifluoromethyl; loweralkoxy, loweralkoxyloweralkyl,loweralkylthioloweralkyl, benzylthioloweralkyl, phenyl orphenylloweralkyl which can be substituted or unsubstituted with aloweralkyl or a halogen such as chlorine, fluorine or iodine attached tothe phenyl moiety; R is one of the group of R' or R and R together withthe 2-carbon atom form a carbocyclic or heterocyclic group, preferablyhaving 3-10 carbon atoms; x is hydrogen, loweralkyl, halogen, hydroxy,alkoxy, trifluoromethyl, amino, nitro or sulfamyl; y and z are any of xor lowercycloalkyl such as cyelohexyl, cyclopentyl; or pyridylunsubstituted or substituted by a radical as one of x; Y is hydrogen,loweralkyl, phenyl, phenylloweralkyl; R R and R are hydrogen, halogen,halomethyl, loweralkyl, cyano, mercapto, loweralkylthio, nitro, amino,loweralkylamino, and loweralkoxy; n is an integer from 0-4; and; (B)pharmaceutically acceptable salts of (A).

Loweralkyl has from 1-8 carbon atoms in a straight chain, andlowercycloalkyl has from 3-8 carbon atoms in the ring.

Representative compounds, inter alia, of the above class are7'-chloro-6'-sulfamyl-3 '-(o-tolyl)-spiro [cyclohexane- 1,2(1H)quinazoline]-4'(3H)-one, 7-chlor0-1'-methyl- 6 sulfamyl 3'(o-tolyl)-spiro[piperidine-4,2-(lH)- quinazoline] 4'(3'H) one, and 2,2dimethyl-3-o-tolyl- 6 sulfamyl 7chloro-1,2,3,4-tetrahydro-4-quinazoline.

The above spiro compounds are made by reacting the N o tolyl 2 amino 4chloro 5 sulfamyl benzamide with cyclohexanone for the first compoundand 1- methyl-4-piperidone for the second compound. The above dimethylcompound is made by reacting N-o-tolyl-2- amino-4-chloro-S-sulfamylbenzamide with acetone in the presence of paratoluene sultonic acid as acatalyst.

Other representative compounds which may be made by the general methodsdescribed above are:

7'-chloro-2-methyl-6'-sulfamyl-3 '-o-tolylspiro [cyclohexane- 1 ,2'( lH-quinazoline] -4 3 'H -one 4,7 '-dichloro-6'-sulfamyl-3'-o-tolylspiro[cyclohexane- 1,2( lH -quinazoline] -4'-(3'H) -one7'-chloro-1-methyl-6'-sulfamyl-3-o-tolylspiro [pyrrolidine- 2,2(1'H)-quinazoline]-4' (3 'H) -one2,2-dimethyl-3-o-t0lyl-6-sulfamy1-7-trifiuoromethyl- 12,3,4-tetrahydro-4-quinazoline2-ethyl-2-methyl-3-o-t0lyl-6-sultamyl-7-chloro-1,2,3 ,4-

tetrahydro-4-quinazoline2-ethyl-2-methyl-3-o-tolyl-6-sulfamyl-7-trifluoromethyl- Il,2,3,4-tetrahydro-4-quinazolineZ-chloromethyl-Z-methyl-3-o-tolyl-6-sulfamyl-7-trifluoromethyl-1,2,3,4-tetrahydro-4-quinazoline3'-benzyl-7-chloro-1-methyl-6'-sulfamylspiro[piperidine- 4,2'(l'H)-quinazoline]-4' (3 'H -one 7'-chloro-3'-phenethyl-6-sulfamylspiro[cyclopentane- 1 2( lH) -quinazoline] 4'- (3 'H) -one 3'-benzyll-methyl-6-sulfamyl-7-trifiuoromethylspiro [piperidine-4,2( lH)-quinazoline]-4( 3'H) -one 3 '-benzyl-7'-chloro-6-sulfamylspiro[cyclopentane-1,2'

lH) -quinazoline] -4' (3 'H -one3'-benzyl-7'-chloro-6-sulfamylspiro[cyc1ohexane-1,2'

1H)quinazoline]-4 (3 'H -one 3 '-benzyl-7 -chloro-6'-sulfamylspiro[piperidine-4,2'

(lH -quinazoline -4- 3 'H -one 2,2- dimethyl-3-phenyl-6-sulfamy1-7-chloro-1,2,3,4-

tetrahydro-4quinazolinone 2-chloromethyl-2-methyl-3-p-tolyl-6-sulfamyl-7-chloro- 1,2,3 ,4-tetrahydro-4-quinazolinone2-ethyl-2-methyl-3-m-tolyl-6-sulfamy1-7-chlo rol ,2, 3,4-

tetrahydro-4-quinazolinone 3'-phenyl-6-sulfamyl-7-trifluoromethylspiro[cyclopentane- 1 ,2'( I'll -quinazoline] -4 3 'H) -one 6'-sulfamyl-3-p-tolyl-7'-trifluoromethylspiro [cyclopentanel ,2 lH) -quinazoline]-4'3'H) -one 7'-chloro-6'-sulfamyl-3'mtolylspiro [cyclopentane-1,2'

lH) -quinazoline1-4'(3H)-one 7 -chloro- 1-methyl-6-sulfamyl-3-p-tolylspiro [piperidine- 4,2 1'H)-quinazoline]-4' 3'H) -one7-chloro-6-sulfamyl-3-p-tolylspiro [cyclohexanel ,2

( 1 'H) -quinazoline] -4' (3 'H -one 4 o-Me 1 o-Me 2 o-Me --CHzN(CH2)a 3o-Me 4 o-Me HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHm... mmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmnrmwwmmw mHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHnnnnnnnnmmmnnnnnnnn m e ...:.N MmmmFwmwmm S HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHit.ititnnnnnnunnnn m 6Hmnmmweeoeeeeeeee tlr OnuHHHHHHanunnHnHHnnnnnnnnnmmwwwrmwwwmmwwmwmmmmmnnannnnnnnn m m .Ll L HMm wb br fimm meeeeeeeeeefleeeeeafleeu66886006966 Ecoonmoooc NsEowoBmomowmmsMMM MMMMM MMMMM MMMMMMM MM MMM A;mpmmppempmwempmmppompp;aizaaaaamaaaaaeaaaaaaaaaazazaaeHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The followingexamples are given to illustrate the invention EXAMPLE I7'-chloro-6'-sulfamyl-3-(o-tolyl)-spiro[cyclohexane- I 60 2 amino4-chloro-5-sulfamyl-N-(o-tolyl)-benzamide 1,2 (1 H) qumazolme] 4 (3 H)one mg.) was slurried in 200 ml. acetic acid. To the slurry 61 was added7.5 gm. of cyclohexanone and 6 drops of concentrat ed sulfuric acid. Themixture was stirred for 5 HNO 3 CONH hours, filtered, washed with etherand dried. The crude 2 2 O 65 product weighed gm. and melted at 279-282.The Ha product was purified by dissolving in 70 ml. dimethylforr'namide,beating to 100 and adding ml. of 100 water. After cooling the productwas filtered, washed twice with 25 ml. of 3:2:DMF:H O, then with 3X ml.methanol and finally with 3X ml. ether. After drying in vacuo overphosphorus pentoxide the product weighed 20.5 gm. and melted at 29l-293.

; N, 10.14; Cl, 8.39; S, 7.84.

EXAMPLE 2 To a mixture of 17 gm. (0.05 mole) of N-o-tolyl-Z-amino-4-chloro-5-sulfamylbenzamide, 175 ml. glacial acetic acid and ml.cyclopentanone was added 25 drops of cone. sulfuric acid. The mixturewas stirred at room temperature. After 2 hours another 10 ml. ofcyclopentanone was added. The mixture wasstirred an additional 4 hoursand another 10 ml. of cyclopentanone was added. After stirring thereaction mixture an additional hours, the solid was filtered washed withglacial acetic acid and air dried. Yield 16.4 gm., M.P. 265268. Aftertwo recrystallizations from 95% ethanol the colorless crystalline solidmelted at 268270.5.

Calc. for C H ClN O S (percent): C, 56.22; H, 4.97; N, 10.35; 01, 8.73;S, 7.90. Found (percent): C, 56.38; H, 5.04; N, 10.35; Cl, 8.44; S,8.06.

EXAMPLE 3 To a mixture of 67.9 gm. (0.2 mole) of N-o-tolyl-Z-amino-4-chloro-5-sulfamylbenzamide, 900 ml. glacial acetic acid and 30gm. (0.265 'mole) of l-methyl-4-piperidone was added dropwise 20 ml.conc. sulfuric acid. The mixture was stirred vigorously at roomtemperature for 24 hours. The glacial acetic acid was decanted from theoil and discarded. The oil was dissolved in 1 liter of water and after 1/2 hours the mixture filtered and the solid discarded. The filtrate wastreated with a saturated solution of sodium carbonate until a pH of 8was reached. Water was added as needed to maintain mobility. Totalvolume of mixture was 3.5 liters. The solid was filtered, washed withwater and air dried. After three recrystallizations from ethanolobtained 60.0 gm. of solvated colorless crystals. Drying product at 131in vacuo for 18 hours yielded a dry product m.p. 219-222.5 (dec.).

Calc. for C H ClN O S (percent): C, 55.23; H, 5.33; N, 12.88; Cl, 8.15;S, 7.37. Found (percent): C, 55.11; H, 5.37; N, 12.91; 01, 8.28; S,7.35, 7.23.

EXAMPLE 4 2,2 dimethyl-3-o-tolyl-6-sulfamyl=7 chloro-1,2,3,4-telrahydro-4-quinazolinoneN-o-tolyl-2-amino-4-chloro-5-sulfamylbenzamide (18 gm., .053 M) wassuspended in a solution of acetone (20 ml.) and acetic acid (10-0 ml.)at room temperature. p-to-luenesulfonic acid (0.2 gm.) was added and thereaction was stirred for two hours. The insoluble solids were filteredand washed with acetic acid and diethyl ether. M.P. 259- 262 C., wt.=20gm. The product was recrystallized from 95% ethanol to give the titlecompound, M.P. 267272, wt.=12 gm.

Analysis-Calc. for C1'1H18C1N3O3S (percent): C, 53.76; H, 4.77; N,11.07; Cl, 9.33; S, 8.44. Found (percent): C, 53.87; H, 4.85; N, 11.04;Cl, 9.32; S, 8.61.

Pharmaceutically acceptable salts of the compounds of group A of thegeneric formula may be made by methods known to the art, and are usefuldiuretics. For example, the sulfamyl group will react with bases to givesodium, potassium or ammonium salts of the quinazolinone compound. Thebasic nitrogen of the quinazolinone can be reacted with acids such ashydrochloric, maleic, tartaric, and the acidic ion exchange resins suchas carboxylic acid, phosphonic acid, and sulfonic acid cation exchangeresins to give the therapeutically elfective and nontoxic salts of thequinazolinone compound.

The following Table I is a summary of pharmacology tests run onrepresentative compounds of this invention. From such tests and otherindications and analogy applicant states that all compounds of thegeneric class first above written are effective diuretics and salureticswith low toxicity. All of the compounds also have low potassiumexcretion and several, as indicated, actually have a negative effect onpotassium excretion, i.e., a lower potassium excretion than the control.

TABLE I No. of Dose,

rats mgJkg. Volume Quantity Structure and name wmmmmm wwmmmm 7 7 0 L7 mwmm 1 1 wmwmww nam mmmwww mm mw 1 1 10.6 gms- -..l

HgN O 18- with a halogen attached to the phenyl moiety; R and R togetherwith the nuclear carbon atom to which they are 65 attached formacycloalkyl group containing 3-10 carbon atoms unsubstituted orsubstituted with chloro; or a nitrogencontaining heterocyclic groupconsisting of 3-10 methylene groups and not more than two NH groupsunsubstituted or substituted with methyl or phenyl; x is 70 hydrogen,loweralkyl, halogen, hydroxy, loweralkoxy, trifluoromethyl, amino, nitroor sulfamyl; y and z are any of x or lowercycloalkyl, or pyridylunsubstituted or substituted by one of x; Y is hydrogen, loweralkyl,phenyl, phenylloweralkyl; R R and R are hydrogen, halogen, 75halomethyl, loweralkyl, cyano, mercapto, loweralkylthio,

or pharmaceutically acceptable salts thereof, in which R is hydrogen,loweralkyl, loweralkoxy, loweralkoxylower- CH!7-chloro-1-methy1-6-suliarnyl-3-(o-to1yl)-spiro (piperidine-4,2(l'H)-quinazolln)-4 (3H)-one I claim: 1. A compound of the formulaY-HNO:S

alkyl, phenylloweralkyl or phenylloweralkyl substituted2,2-dimethyHiotoIyI-B-suliamyl-7-ehloro-1,2,3,4- tetrahydroquinazolinone13 nitro, amino, loweralkylamino, or loweralkoxy; n is an integer from0-4.

2. The compound of claim 1 wherein the recited groups of the formula aresuch that the compound is 7 chloro6'-sulfamyl-3'-(o-tolyl)-spiro[cyclohexane- 1,2'(1H)quinazoline]-4(3H)-one 3. The compound of claim 1 wherein the recitedgroups of the formula are such that the compound is 7'-chloro- 6'sulfamyl 3-(o-tolyl)-spiro[cyclopentane-1,2'(1'H)- quinazol-ine] -4 (3H)-one 4. The compound of claim 1 wherein the recited groups of theformula are such that the compound is 7'-chloro- 1 methyl 6' sulfamyl3'-(o-to1y1)-spiro[piperidine- 4,2 1H) -q,uinazoline] -4 (3H) oneReferences Cited FOREIGN PATENTS 926,038 5/1963 Great Britain.

5 OTHER REFERENCES Chem. Abstracts, 63: l3286d-e (1965).

ALEX MAZEL, Primary Examiner 10 R. J. GALLAGHER, Assistant Examiner US.Cl. X.R. 424251 Patent No. 3, 518,392 Dated June 30, 1970 Inventor(s)301A VITHAL SI'IETTY It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Colmm 2, lines 9, 11, 23, 25, 27, 37, 39, 41, 43, 45, 47, 55, 57, 59, 61and 63, "quinazoline" should be --quinazolin--.

Column 2, lines 12, 29, 31, 33 and 35, "quinazoline" should be-quinazolinone-.

Column 7, line 61, "quinazoline" should be --quinazol1n- Column 11,Claim 1, in the structural formula, "R should be --R and "R should be "RColumn 13, Claims 2, 3 and 4, last line of each claim, "quinazoline"should be --quinazo1in--.

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